The present invention relates to methods of treating adult onset diabetes by administering to a patient in need thereof an effective amount of a lectin capable of inducing a decline in food intake and inducing hypoglycemia. The present invention also relates to methods of inducing weight loss by administering an effective amount of a lectin capable of inducing a decline in food intake and repeating the administering step to maintain the decline in food intake. In particular, the present invention relates to methods of treating adult-onset diabetes and inducing weight loss with the mixture of lectins known as pokeweed mitogen and the bitter pear melon lectin.
Adult-onset Type II diabetes mellitus is a major health problem in this country. Because it is exacerbated by obesity, treatment of this disease is often two-pronged, using drugs to maintain normal blood glucose concentrations and diet therapy to promote weight loss. However, current hypoglycemia drugs are not always effective, and adherence to diet therapy is generally poor.
Lectins are a general class of proteins that bind to carbohydrates. The binding of these lectins to carbohydrates that are part of cell membrane receptors can result in cell activation. This is particularly well characterized with cells of the immune system. Lectins are widely used to stimulate immune function in in vitro studies.
The crude extract of the lectins from the pokeweed plant, Phytolacca americana is referred to as pokeweed mitogen. Pokeweed mitogen is a mixture of five lectins, which are designated as Pa-1 to Pa-S. These range in size from 19 to 30 kD, and contain approximately 3 percent carbohydrate. The ligand for all the pokeweed lectins is N-acetyl glucosamine. Despite binding to the same ligands, there is a disparity between the bioactivity of the five pokeweed mitogen lectins. Only Pa-1 is a polymer, and only Pa-1 stimulates B cells. Further, Pa-2 to Pa-5, all of which stimulate T cells, do so with widely differing potency.
Effects attributed to pokeweed mitogen include stimulation of the immune system, with the appearance of plasma cells in the peripheral circulation, the release of interferon-y and tryptophan metabolites, and transient splenomegaly secondary to blood engorgement. Zazula et al., P.S.E.B.M., 133, 1088-92 (1970), disclosed that the intravenous injection of pokeweed mitogen to mice produced a marked increase in the weight of the spleen, with an increase in the number of nucleated cells, lymphoblasts, and mitotic figures. A marked increase in the total number of plasma cells was also produced, but these cells did not appear in the peripheral blood, and the effect of pokeweed mitogen was limited to a transient leukopenia. One to three days after the administration of pokeweed mitogen at a level of 175 mg/kg, all mice lost an average of 1.5 g of body weight, but by day five showed a net weight gain. Weight loss following pokeweed mitogen infusion is not consistently reported in the literature.
Wheat germ agglutinin is a lectin that shares structural and binding properties with pokeweed mitogen lectins. Mice given wheat germ agglutinin developed a non-significant hypoglycemia and a decline in food intake, but no weight loss. Like Pa-2 to Pa-5, wheat germ agglutinin stimulates T cells.
There exists a need for a pharmaceutical composition for the treatment of diabetes mellitus that produces both a lowered circulating glucose level and an anorexic state that results in the loss of body weight.
This need is met by the present invention. It has now been discovered that a chloroform precipitatable fraction of pokeweed mitogen likely to be lectin Pa-1 not only possesses the insulinomimetic properties of wheat germ agglutinin, thereby producing a decline in circulating glucose levels by binding to cell insulin receptors, but, unlike wheat germ agglutinin, Pa-1 also binds to insulin receptors in the brain to produce an anorexic state and consequent weight loss. It has further been discovered that the lectin from the bitter pear melon Momordica charantia also induces hypoglycemia and an anorexic state and consequential weight loss to a degree equivalent to that induced by the Pa-1 chloroform precipitate.
Therefore, according to one aspect of the present invention, there is provided a method of treating adult-onset diabetes in a mammal in need thereof by administering to the mammal a pokeweed mitogen chloroform precipitatable fraction in an amount between about 1 and about 100 micrograms per kilogram of body weight that is effective to induce hypoglycemia in said mammal.
According to another aspect of the present invention there is provided a method of treating adult-onset diabetes in a mammal in need thereof by administering to the mammal a dosage form consisting essentially of Momordica lectin in an amount effective to induce hypoglycemia in the mammal. Preferred methods in accordance with this aspect of the present invention further include the step of continuing the administering step to maintain the hypoglycemia state. The preferred dosage amount is between about 1 and about 100 micrograms per kg of body weight per day, and even more preferable is an amount effective to induce a decline in food intake. An even more preferred method continues the administering step daily until the decline in food intake produces a weight loss of at least about 10 percent.
The lectins of the present invention also induce a decline in food intake and consequential weight loss and may be administered advantageously to any patient who would obtain a health benefit from a loss of weight. Therefore, according to another aspect of the present invention, there is provided a method of inducing weight loss in a mammal in need thereof by administering to the mammal a lectin selected from a pokeweed mitogen chloroform precipitatable fraction and Momordica lectin in an amount between about 1 and about 100 micrograms per kg. of body weight per day that is effective to stimulate a decline in food intake in the mammal, and continuing the administering step to maintain the decline in food intake.
The present invention incorporates the discovery that the lectins of the present invention may be administered in an amount that stimulates a decline in food intake without inducing hypoglycemia. Therefore, preferred weight loss methods according to the present invention administer to the mammal a pokeweed mitogen chloroform precipitatable fraction or Momordica lectin in an amount effective to induce a decline in food intake in the mammal without inducing hypoglycemia.
However, dosage levels that induce both a decline in food intake and hypoglycemia may be advantageously employed in the treatment of adult-onset diabetes to control both blood sugar levels and patient weight. Therefore, according to another aspect of the present invention, there is provided a method of treating adult-onset diabetes in a mammal in need thereof by administering to the mammal a dosage form consisting essentially of Momordica lectin in an amount effective to induce a decline in food intake and induce hypoglycemia in the mammal, and repeating the administering step daily until the decline in food intake produces a weight loss of at least about 10%.
The present invention also includes pharmaceutical compositions consisting essentially of an effective amount of lectin selected from pokeweed mitogen chloroform precipitatable fraction and Momordica lectin, and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may be in either oral or systemic dosage forms.
While not being bound by any particular theory, it is believed that pokeweed mitogen chloroform precipitatable fraction and Momordica lectin produced weight loss in addition to hypoglycemia by crossing the blood-brain barrier and binding to insulin receptors in the brain. It is believed that other lectins that produced only hypoglycemia without a corresponding weight loss are capable of binding to cell membrane insulin receptors to increase cellular glucose uptake and reduce circulating glucose levels, but are incapable of crossing the blood-brain barrier to bind to insulin receptors in the brain.
While weight loss following pokeweed mitogen infusion was not consistently shown in the prior art literature, the contradictory findings are believed to have resulted from differing preparations of the pokeweed mitogen, with the predominance of different forms of the lectins. The present invention incorporates the discovery that in order to obtain consistent weight loss, a pokeweed mitogen chloroform precipitatable fraction must be employed.
The above and other objects, features and advantages of the present invention will become clear from the following description of the preferred embodiments considered in conjunction with the accompanying drawings.